The long term objectives of the proposed research are to understand the role of the earliest born neurons in histogenesis of the cerebral cortex. The hypotheses that the earliest born neurons are unique, that they play a role in establishment of cortical connectivity, and that they are involved in establishment of differences among cortical areas will be tested Development of normal cortical function requires proper development of neuronal connectivity and transmitter expression. Interference with the normal sequence of events during any phase of cortical development can result in behavioral and cognitive disabilities ranging from subtle to severe. The proposed studies will focus on the earliest born neurons of the cerebral cortex. The timing and rate of neuron death in the earliest born neurons will be compared with the timing and rate of neuron death in two later born populations. The neurotransmitter and/or neuropeptide expressed by the earliest born neurons which die and those which survive will be examined to determine whether and when specific neuronal populations are selectively eliminated. To determine whether the earliest born neurons may be involved in specification of cortical areas, developmental patterns of expression of neuropeptides in 5 well-defined cortical areas will be compared. The population of neurons which participate in the initial formation of the callosal pathway will be identified, and the potential role of particular neurotransmitters or neuropeptides in growth cone guidance and axon branching will be assessed. The timing and extent of exuberance in the supragranular and infragranular callosal cells will be examined to determine whether or not axon withdrawal occurs in the neurons which pioneer the callosal pathway. Experiments will be done to determine whether or not callosal axons reach the contralateral hemisphere before their parent cell bodies complete migration, and whether not the neurons which send out the first callosal axons subsequently die.